Tumor-associated macrophages (TAM) promote triple-negative breast cancer (TNBC) progression. Here, we report BRCA1-IRIS-overexpressing (IRISOE) TNBC cells secrete high levels of GM-CSF in a hypoxia-inducible factor-1α (HIF1α)- and a NF-κB-dependent manner to recruit macrophages to IRISOE cells and polarize them to protumor M2 TAMs. GM-CSF triggered TGFβ1 expression by M2 TAMs by activating STAT5, NF-κB, and/or ERK signaling. Despite expressing high levels of TGFβ1 receptors on their surface, IRISOE TNBC cells channeled TGFβ1/TβRI/II signaling toward AKT, not SMAD, which activated stemness/EMT phenotypes. In orthotopic and syngeneic mouse models, silencing or inactivating IRIS in TNBC cells lowered the levels of circulating GM-CSF, suppressed TAM recruitment, and decreased the levels of circulating TGFβ1. Coinjecting macrophages with IRISOE TNBC cells induced earlier metastasis in athymic mice accompanied by high levels of circulating GM-CSF and TGFβ1. IRISOE TNBC cells expressed low levels of calreticulin (the "eat me" signal for macrophages) and high levels of CD47 (the "do not eat me" signal for macrophages) and PD-L1 (a T-cell inactivator) on their surface. Accordingly, IRISOE TNBC tumors had significantly few CD8+/PD-1+ cytotoxic T cells and more CD25+/FOXP3+ regulatory T cells. These data show that the bidirectional interaction between IRISOE cells and macrophages triggers an immunosuppressive microenvironment within TNBC tumors that is favorable for the generation of immune-evading/stem-like/IRISOE TNBC metastatic precursors. Inhibiting this interaction may inhibit disease progression and enhance patients' overall survival. SIGNIFICANCE: The BRCA1-IRIS oncogene promotes breast cancer aggressiveness by recruiting macrophages and promoting their M2 polarization.

中文翻译：

---

与肿瘤相关的巨噬细胞的双向相互作用诱导BRCA1-IRIS过表达的TNBC肿瘤中的免疫抑制微环境。

肿瘤相关巨噬细胞（TAM）促进三阴性乳腺癌（TNBC）进展。在这里，我们报告BRCA1-IRIS过表达（IRISOE）TNBC细胞以低氧诱导因子-1α（HIF1α）-和NF-κB依赖性方式分泌高水平的GM-CSF，从而将巨噬细胞募集到IRISOE细胞并使它们极化促进M2 TAM的发展。GM-CSF通过激活STAT5，NF-κB和/或ERK信号触发M2 TAM触发TGFβ1表达。尽管在其表面表达高水平的TGFβ1受体，但IRISOE TNBC细胞通过TGFβ1/TβRI/ II信号传导至AKT而非SMAD，从而激活了干性/ EMT表型。在原位和同基因小鼠模型中，TNBC细胞中的IRIS沉默或失活降低了循环GM-CSF的水平，抑制了TAM募集，并降低了循环TGFβ1的水平。将巨噬细胞与IRISOE TNBC细胞共注射可在无胸腺小鼠中引起较早的转移，并伴有高水平的循环GM-CSF和TGFβ1。IRISOE TNBC细胞在其表面表达低水平的钙网蛋白（巨噬细胞“吞噬我”信号）和高水平的CD47（巨噬细胞“不吞噬我”信号）和PD-L1（T细胞灭活剂）。因此，IRISOE TNBC肿瘤的CD8 + / PD-1 +细胞毒性T细胞明显较少，而CD25 + / FOXP3 +调节性T细胞却较多。这些数据表明，IRISOE细胞与巨噬细胞之间的双向相互作用触发了TNBC肿瘤内的免疫抑制微环境，这有利于产生免疫逃避/类干/ IRISOE TNBC转移性前体。抑制这种相互作用可能会抑制疾病进展并增强患者的抵抗力 总体生存率。意义：BRCA1-IRIS癌基因可通过募集巨噬细胞并促进其M2极化来促进乳腺癌的侵袭性。